The mammalian genome is ubiquitously transcribed and the ends of telomeres are no exception. In spite of their heterochromatic properties, telomeric ends actively synthesize a heterogeneous population of long noncoding RNAs dubbed “TERRA” (Azzalin et al., 2007; Schoeflner and Blasco, 2007; Zhang et al., 2009). TERRA transcripts range in size from 100 bases up to >9 kb and contain the canonical telomeric repeat sequence, UUAGGG, as well as sequences unique to the sub-telomeric region of each chromosome. The function of TERRA has generated major interest in light of its association with human diseases, such as cancer and the ICF syndrome (immunodeficiency, centromere instability, and facial anomalies) (Maicher et al., 2012; Azzalin and Lingner, 2015). Elegant studies have pointed to a number of telomere-associated functions. Telomeres are well-defined nucleoprotein complexes that cap the physical ends of linear chromosomes and protect them from unprogrammed shortening and genetic rearrangements (Blackburn et al., 2006; Sfeir and de Lange, 2012; Bernardes de Jesus and Blasco, 2013; Doksani and de Lange, 2014; Azzalin and Lingner, 2015). The reverse transcriptase activity of the RNA-containing telomerase complex enables regeneration of chromosomal ends that are lost with every DNA replication (Lingner et al., 1997). However, TERRA's activity does not appear to be directly related to telomerase activity (Schoeftner and Blasco, 2007; Redon et al., 2010; Redon et al., 2013). Rather, TERRA seems to keep telomere length in check (Sandell et al., 1994; Luke et al., 2008; Maicher et al., 2012; Pfeiffer and Lingner, 2012; Pfeiffer et al., 2013; Wang et al., 2015), regulate recombination (Balk et al., 2013; de Silanes et al., 2014; Yu et al., 2014), and serve as a scaffold for recruitment of HP1, histone methyltransferases, and shelterins to telomeric heterochromatin (Deng et al., 2009). Thus, TERRA is an integral part of the telomeric architecture.
Cytological studies indicate that only about half of detectable TERRA transcripts are localized to telomeres (Le et al., 2013). The remaining half is presumed to be “free” in the nucleoplasm. Nevertheless, investigation into TERRA function has focused almost exclusively on telomeres, though early observations noted a large cluster of TERRA transcripts near the inactive X-chromosome (Xi) of somatic female cells (Schoeftner and Blasco, 2008; Zhang et al., 2009). TERRA RNA is also concentrated next to the Y-chromosome (Zhang et al., 2009).